Malignant mesothelioma (MM) are relatively rare and highly aggressive neoplasms, arising from the uncontrolled proliferation of mesothelial cells lining serosal cavities, most commonly the pleura (Malignant Pleural Mesothelioma or MPM) (Robinson et al. (2005) Lancet 366:397-408). Epidemiologic studies have established that exposure to asbestos is one of the most important MPM etiologic factor in industrialized countries (Gruber (2005) Lung Cancer 49S1:S21-S23; Bartrip (2004) Postgrad Med. J. 80:72-76). Although worldwide usage of asbestos has been considerably reduced, the incidence of mesothelioma is expected to rise in the next two decades, because of a long latency period (20 to 40 years) between asbestos exposure time and clinical symptoms apparition.
Today, cancer diagnosis is usually established at an advanced stage because of the absence of overt symptoms in the early period of the disease, thus making poor the prognosis for mesothelioma patients. Consequently, MPM is actually considered as a cancer relatively refractory to all conventional treatment modalities. Accordingly, there is a pressing need for the development of new therapeutic approach.
During the past decade, there has been an increasing interest in virotherapy, partly related to the growing knowledge in the production of recombinant viral vectors for human gene therapy. Numerous RNA replicating viruses are now considered as potential cancer therapeutics. As such, therapy of MPM using engineered replication-competent Herpex Simplex Viruses (HSV) has been proposed, based on in vitro studies and results obtained on a murine model of MPM (Adusumilli et al. (2006) J. Gene Med. 8:603-615). However, the long term safety of these engineered viral vectors in humans is not known and extensive clinical trials will be necessary to document this aspect of HSV usage.
Accordingly, there is a need for viral vectors with recognized safety liable to be used in the frame of mesothelioma treatment.
MV (Measles Virus) is an enveloped, negative single strand RNA virus belonging to the Paramyxoviridae family, genus Morbilli virus. Various replication-competent live attenuated strains of MV have been developed for producing vaccines against measles. By way of example, Schwartz, Moraten, or Zagreb (which are derived from MV samples isolated from an Edmonston patient) are safe and well-documented MV vaccine strains.
It has been shown recently that in vivo administration of a replication-competent Edmonston MV strain resulted in growth slowing or sometimes regression of tumors established animal models of lymphoma and myeloma cancer (Grote et al. (2001) Blood 97:3746-3754; Peng et al. (2001) Blood 98:2002-2007). Besides, Anderson et al. (2004) Cancer Res. 64:4919-4926, have shown in in vitro experiments that high CD46 expression by tumor cells was necessary for the infection and the killing of these cells by a live attenuated Edmonston MV strain. However, it is known that CD46 is variably expressed by human carcinomas (Niehans et al. (1996) American J. Pathol. 149:129-142), thereby casting doubts on the general applicability of live attenuated MV strains for treating cancers.